ERG Is a member of the ETS transcription factor family that has recently been shown to participate in the regulation of selected endothelial-restricted genes including vWF, endoglin, and VE-cadherin. Our preliminary studies demonstrate several unique features of ERG. First, ERG exhibits a highly endothelial cell (EC)-restricted expression pattern throughout vascular development and in several adult tissues. Second, during embryonic stem (ES) cell differentiation, ERG is first expressed in a subset of VEGF-R2+ cells that also express VE-cadherin. Third, ERG closely tracks with stem cells that differentiate along the endothelial lineage. Fourth, downregulation of ERG in ES cells markedly inhibits EC differentiation and vascular structure formation in embryoid bodies (EB). The overall hypothesis for this proposal is that ERG is a critical transcriptional regulator of EC differentiation and vascular development. Aim I will define the role of ERG during vascular development. ERG is expressed in an EC-restricted pattern within several tissues and organs during early stages of vascular development. The hypothesis for this aim is that ERG expression is required for vascular development. Aim II will define the transcriptional and epigenetic regulation of endothelial differentiation by ERG The hypothesis for this aim is that ERG functions at multiple levels to regulate EC differentiation. ERG may act alone or in combination with other transcription factors to regulate EC-specific target genes such as VE-cadherin. Aim III will examine the role of ERG in regulating EPC function and postnatal vasculogenesis Endothelial progenitor cells (EPC) represent an important cell type that can promote vascular repair, angiogenesis and post-natal vasculogenesis. The hypothesis for this aim is that ERG is a critical transcriptional regulator of EPC function and post-natal vasculogenesis.